Abstract 10615: The Effects of Maternal Hypothyroidism on Progeny Cardiac Development and Disease Susceptibility

Abstract

Introduction: Maternal hypothyroidism (MH) is a common clinical condition with high prevalence. MH is thought to have adverse effects on progeny's cardiac development and disease susceptibility. Hypothesis: MH impacts progeny's postnatal cardiac development and the susceptibility to adverse cardiac disease responses as adults. Methods: MH model was induced by thyroidectomy (TX) with total thyroxine (TT4) under 1ng/dl after surgery. Offspring of mice that underwent TX or Sham surgery was termed THD (Deficient) and THN (Normal) animals. Hearts were collected from THD and THN animals to determine heart weight, cardiomyocyte (CM) size, and CM proliferation. Transverse Aortic Constriction (TAC) was performed to induce pressure overload-induced cardiac hypertrophy and/or heart failure (HF) model in adult THD and THN mice. ECHO (in-vivo) and histological (in-vitro) were performed at specific times after TAC. RNA-seq was performed at embryo day (E) 18.5 and Postnatal day 5 (P5) using heart tissue. Results: The postnatal TT4 level was not different between the THD and THN mice. The heart weight (HW) to body weight (BW) ratio was similar between the two groups on P7, P14, and P60, but the THD mice had larger CM sizes. EdU+, Ki67+, and PH3+ CMs were lower in THD progenies on P0, P5, and P13. RNA-seq data showed that the genes related to cell division and DNA replication were downregulated in THD mice on E18.5 and P5, respectively. In adult animals six weeks after TAC, the THD mice had a greater HW/BW ratio and lung weight(LW) to BW ratio, consistent with more severe cardiac hypertrophy and HF than the THN mice. After TAC, THD mice had a lower LVEF, higher absolute E/e' ratio, greater end-diastolic pressure, and more severe LV fibrosis than THN mice. Conclusions: Alterations in CM proliferation during fetal and early postnatal development results in fewer adult CMs in animals from MH mothers. These changes are associated with increased disease susceptibility in adult MH progeny.